Holoprosencephaly (HPE) results from an incomplete midline cleavage of the forebrain (prosencephalon) and includes a wide spectrum of intracranial and craniofacial midline defects, along with a myriad of clinical manifestations, which consist of neurologic impairment and dysmorphism of the brain and face. Evidence suggests that holoprosencephaly can be present either sporadically or have a syndromic association. The defect associated with holoprosencephaly occurs at around two to three weeks after conception and is a disorder of gastrulation.
On the whole, the most studied cases of holoprosencephaly are those occurring due to chromosomal anomalies but with normal karyotype. They are rarely associated with malformation syndromes. The majority of live births with HPE have a ‘nonsyndromic, nonchromosomal HPE, which describes HPE that cannot be attributed to chromosomal or syndromic causes and includes environmental causes, deletions of or mutations in genes known to be involved in HPE, or currently unidentifiable factors.
From the above discussion, it can be concluded that the etiology of holoprosencephaly can be divided into-
Nonsyndromic monogenic causes: SHH anomalies are the most common defects that have been recorded in HPE patients with associated midline defects. Other main genetic causes include ZIC2, SIX3, and TGIF.
Syndromic causes: Around 32-42 % of the cases occur due to anomalies of chromosome number, most commonly trisomy 13, followed by trisomy 18 and triploidy.
Specific syndromes related to HPE include both autosomal dominant and autosomal recessive syndromes including-
2) FGFR1 gene-related Kallman syndrome two and Hartsfield syndrome
2) DHCR7 gene-related Smith-Lemli-Opitz Syndrome
HPE is associated with pregestational maternal diabetes. Consistent maternal folic acid use appears to be protective. Animal studies suggest HPE can result from exposure to teratogens, such as ethanol, retinoic acid, food-borne mycotoxins like ochratoxins, cyclopamine (Hedgehog signaling inhibitors), and drugs that interfere with cholesterol biosynthesis.
Holoprosencephaly occurs rather frequently, and is observed in 1:250 conceptuses; due to a high rate of fetal demise, the birth prevalence is between 1:8000 to 1:16000 live births and is similar among different international populations. In the United States, seemingly higher prevalence rates have been reported in African-American, Hispanic, and Pakistani ethnicities, most likely attributable to decreased prenatal diagnosis and termination rates in these groups.
To understand the pathogenesis of holoprosencephaly, one must understand the relationship between the development of the face and the brain. The successful development of the brain and face occurs due to reciprocal signaling of several 'signaling molecules' between the surface ectoderm and neural crest cells that determine the migration of primitive embryonal cells, leading to the formation of highly developed structures. Incomplete diverticulation and cleavage of the embryonic forebrain is the reason for the intracranial pathology. Blocking this signaling alters the dorso-ventral polarity, anterior-posterior axis, and inhibits bilateral symmetry of the forebrain. Shh is one such signaling molecule. Inhibiting Shh expression in the basal telencephalon subsequently impedes the dorso-ventral polarity and inhibits the induction of Shh expression in the Frontonasal Ectodermal Zone (FEZ), leading to multiple midline facial defects. Various degrees of a block in the Shh signaling determine the severity of the disease manifestation.
Incomplete penetrance and variable expressivity make it difficult to predict disease manifestation in the offspring. The parents carrying defined mutations may not have either physical or neurological symptoms. Current studies suggest a multi-hit origin of HPE, explaining the lack of clinical manifestations in patients presenting with the concerned mutations.
A standardized diagnostic protocol, including dysmorphology examination, complete family history and ascertainment of risk factors, and neuroimaging, would cover the spectrum of presenting features of these disorders.
The pathogenesis of holoprosencephaly is related to abnormal genes that are responsible for the normal development of the head and the face. Hence, clinically, the spectrum of the presentation can range from mild craniofacial defects, like single maxillary central incisor with normal neurological function, to severe cranio-facio-neurological defects like cyclopia or proboscis with an alobar variant. In moderate to severe cases, the craniofacial symptoms have proven to be an indicator of the severity of the intracranial lesion.
Severe facial phenotypes are associated with the alobar variant of holoprosencephaly and include-
Less severe facial phenotypes are associated with the following intracranial manifestations including-
Individuals with a mild variant of holoprosencephaly, usually have a relative with frank holoprosencephaly. These patients typically present with only the craniofacial anomalies without the accompanying neurological defect.
In a pediatric patient fulfilling the above mentioned clinical triad of typical morphology, family history, and environmental factors, the next step is to confirm the type of intracranial anomaly by neuroimaging. Evaluation of holoprosencephaly can take place as early as the prenatal period. This is done by ultrasonography and MRI. In severe forms of holoprosencephaly, a USG can detect the anomaly as early as the first trimester. An MRI is used for diagnosis in the third trimester. Postnatal neuroimaging includes USG, which is the preferred imaging modality in infants with open anterior fontanelles. In older children, a CT or MRI may be considered. However, they come with their own risks. While the CT could cause excess radiation exposure, the risk of excess sedation exists with MRI. The pattern observed in imaging could include:
Alobar holoprosencephaly: This occurs due to diffuse cortical nonseparation, the corpus callosum and olfactory bulbs are absent entirely. The deep gray nuclei are fused, and a single midline ventricle is seen in these patients.
Semilobar form: There exists nonseparation of the frontal lobes, the anterior corpus callosum is absent, fused deep gray nuclei, and absent anterior horns of lateral ventricles.
Lobar forms: Nonseparation of basal frontal brains, absent corpus callosum adjacent to affected areas with hypoplastic olfactory bulbs, and the azygous anterior cerebral artery (anteriorly displaced) is associated with this defect.
Middle intrahemispheric variant: Nondisjunction between bilateral frontal and parietal lobes, an absent body of the corpus callosum, and azygous anterior cerebral artery are visible in these patients.
Once the diagnosis is confirmed, the patient is evaluated for a syndromic association. This changes the course of management in that it includes the evaluation of the coexisting features that may exist and might require further medical or surgical attention.
Following this, genetic testing is carried out to determine the existence of any chromosomal anomaly by conducting cytogenetic and molecular testing. If this reveals any kind of chromosomal or genetic anomaly that is associated with holoprosencephaly, it would further mandate genetic counseling for the parents, should they decide to conceive another child.
The management in patients with holoprosencephaly is symptomatic and requires a multidisciplinary approach. It targets each organ system, and the related complications, individually.
Septo-optic dysplasia: In addition to enlarged ventricles and hypothalamo-pituitary axis failure, it also consists of optic nerve degeneration and absent septum pellucidum, which are both absent in holoprosencephaly.
DiGeorge syndrome: Abnormalities such as cleft palate, hypertelorism, are associated with other anomalies like cardiopulmonary anomalies like aortic arch anomalies and conotruncal defects. Other anomalies like T cell deficiency and signs of hypocalcemia as a result of parathyroid hypoplasia are seen as well.
Hydranencephaly: A CT of the head shows absent bilateral cerebral hemispheres with no cortical mantle, and a fluid-filled cavity. However, since the entire falx is preserved, this rules out holoprosencephaly.
Porencephalic cyst: On MRI, it appears as an abnormal accumulation of CSF within the brain parenchyma, rather than an absence/midline fusion of cerebral lobes, as seen in holoprosencephaly.
Arachnoid cyst: This occurs in conjunction with HPE or could be the only finding. It occurs secondary to trauma or could be inherited in an autosomal manner. It does not present with facial defects unless coexisting holoprosencephaly exists.
Moderate to severe cases of HPE generally have a poor prognosis. the mortality rate increases as follows, with 33% in the first 24 hours after birth, to 58% in the 1 month, to 50% between the 4 and the 5 months, to between 70% to 80% in the 1 year of life. The survival rate after 1 year of life is only around 29%. A very small number survive until adulthood. Mild to moderate cases typically survive till adulthood, but live with the accompanying complications.
Neurological complications associated with holoprosencephaly include epilepsy with or without clinically evident seizure activity, motor impairment such as hypotonia and dystonia, with or without spasticity. Hydrocephalus is a common complication with the alobar variant of holoprosencephaly, thus presenting with a macrocephaly rather than microcephaly, sometimes clouding the initial clinical suspicion.
Gastrointestinal tract anomalies like poor gastric and colonic motility and gastroesophageal reflux are a result of poor neuronal migration during development.
Additionally, the hypothalamus being a midline structure is unformed in these patients. Non-formation of the hypothalamus is associated with various endocrinal symptoms due to pituitary hormone deficiency, along with impaired homeostatic functions like thirst, hunger, and temperature. Hormone irregularities of the posterior pituitary are far more common than those of the anterior pituitary. Patients must be screened repeatedly for electrolyte levels to diagnose diabetes insipidus. Regarding the anterior pituitary insufficiency, both hypothyroidism and hypocortisolism can prove to be lethal, while growth hormone and gonadotrophic hormone deficiency can lead to stunting and sexual immaturity.
Genetic testing is recommended for the parents with a child showing apparent symptoms or in those showing mild variants. However, the indication for testing depends on the clinical suspicion of the disease, which itself is very difficult given the numerous phenotypic variations. Compounding the diagnosis further is the numerous number of genes involved along with a multi-hit process. The de-novo occurrence of some mutations which show a specific defect in the parents has also been observed. In this case, the chances of HPE in a subsequent pregnancy are greatly reduced.
Here are some important points
An interprofessional team provides a holistic and integrated approach to accurately diagnose and help achieve the best possible outcomes. The complications that commonly accompany holoprosencephaly require a multidisciplinary approach. Endocrine dysfunction that commonly accompanies some variants of HPE should be treated life long by a pediatric endocrinologist. Associated gastrointestinal anomalies are attended to by pediatric gastroenterologists. Neurological anomalies like seizures, movement disorders, facial anomalies, and hydrocephalus, are attended to by the neurologist and the neurosurgeon.
Dysphagia or reflux related to the cleft palate is treated by a plastic surgeon in conjunction with the pediatric surgeon. The importance of psychological aid and genetic counseling must not be undermined and should be offered to all parents. Child psychiatrists and psychologists can be consulted for the emotional and behavioral consequences of holoprosencephaly.
Collaboration with shared decision making and good communication among the interprofessional team is key for a good outcome. The interprofessional care provided to the patient must use an integrated care pathway combined with an evidence-based approach to planning and evaluation of all joint activities. The earlier signs and symptoms of a complication are identified, the better is the prognosis and outcome.
|||Raam MS,Solomon BD,Muenke M, Holoprosencephaly: a guide to diagnosis and clinical management. Indian pediatrics. 2011 Jun; [PubMed PMID: 21743112]|
|||Srivastava K,Hu P,Solomon BD,Ming JE,Roessler E,Muenke M, Molecular analysis of the Noggin (NOG) gene in holoprosencephaly patients. Molecular genetics and metabolism. 2012 Jun; [PubMed PMID: 22503063]|
|||Tekendo-Ngongang C,Muenke M,Kruszka P, Holoprosencephaly Overview 1993; [PubMed PMID: 20301702]|
|||Kauvar EF,Muenke M, Holoprosencephaly: recommendations for diagnosis and management. Current opinion in pediatrics. 2010 Dec; [PubMed PMID: 20859208]|
|||Geng X,Oliver G, Pathogenesis of holoprosencephaly. The Journal of clinical investigation. 2009 Jun; [PubMed PMID: 19487816]|
|||Petryk A,Graf D,Marcucio R, Holoprosencephaly: signaling interactions between the brain and the face, the environment and the genes, and the phenotypic variability in animal models and humans. Wiley interdisciplinary reviews. Developmental biology. 2015 Jan-Feb; [PubMed PMID: 25339593]|
|||Ming JE,Muenke M, Multiple hits during early embryonic development: digenic diseases and holoprosencephaly. American journal of human genetics. 2002 Nov; [PubMed PMID: 12395298]|
|||Kruszka P,Martinez AF,Muenke M, Molecular testing in holoprosencephaly. American journal of medical genetics. Part C, Seminars in medical genetics. 2018 Jun; [PubMed PMID: 29771000]|
|||Golden JA, Towards a greater understanding of the pathogenesis of holoprosencephaly. Brain [PubMed PMID: 10598051]|
|||Aruna E,Chakravarthy VK,Rao DN,Rao DR, Holoprosencephaly with multiple anomalies of the craniofacial bones-an autopsy report. Journal of clinical and diagnostic research : JCDR. 2013 Aug; [PubMed PMID: 24086891]|
|||Dubourg C,Bendavid C,Pasquier L,Henry C,Odent S,David V, Holoprosencephaly. Orphanet journal of rare diseases. 2007 Feb 2; [PubMed PMID: 17274816]|
|||Honey EM,Bütow KW,Zwahlen RA, Holoprosencephaly with Clefts: Data of 85 Patients, Treatment and Outcome: Part 1: History, Subdivisions, and Data on 85 Holoprosencephalic Cleft Patients. Annals of maxillofacial surgery. 2019 Jan-Jun; [PubMed PMID: 31293943]|
|||Sarica C,Yucetas C,Ozen A,Ucler N,Konca C,Akar S, Management Strategies for Hydrocephalus in Alobar Holoprosencephaly: A Case Report and Discussion. Pediatric neurosurgery. 2018; [PubMed PMID: 29902800]|
|||Maurya VK,Ravikumar R,Bhatia M,Rai R, Septo-optic dysplasia: Magnetic Resonance Imaging findings. Medical journal, Armed Forces India. 2015 Jul; [PubMed PMID: 26286097]|
|||Lackey AE,Muzio MR, DiGeorge Syndrome 2020 Jan; [PubMed PMID: 31747205]|
|||Khalid M,Khalid S,Zaheer S,Redhu N,Ekramullah, Hydranencephaly: a rare cause of an enlarging head size in an infant. North American journal of medical sciences. 2012 Oct; [PubMed PMID: 23112982]|
|||El Hasbani G,Balaghi A,Assaker R,Rojas A,Troya M,Kofahi A,Assaker JP,Diab C,Al Husayni H, Intraparenchymal hemorrhage and cerebral venous thrombosis in an adult with congenital porencephalic cyst presenting for generalized tonic-clonic seizures. Radiology case reports. 2020 Jan; [PubMed PMID: 31762865]|
|||Xiong J,Xiang B,Chen X,Cai T, Case report: a novel mutation in ZIC2 in an infant with microcephaly, holoprosencephaly, and arachnoid cyst. Medicine. 2019 Mar; [PubMed PMID: 30855487]|
|||Levey EB,Stashinko E,Clegg NJ,Delgado MR, Management of children with holoprosencephaly. American journal of medical genetics. Part C, Seminars in medical genetics. 2010 Feb 15; [PubMed PMID: 20104615]|
|||Buljac-Samardzic M,Doekhie KD,van Wijngaarden JDH, Interventions to improve team effectiveness within health care: a systematic review of the past decade. Human resources for health. 2020 Jan 8; [PubMed PMID: 31915007]|